Successful application of potential neuroprotective agents will depend on early detection of neuronal and glial abnormalities before significant cell loss occurs. The long-term goal of this work is to establish non-invasive, quantitative magnetic resonance spectroscopy (MRS) measures sensitive to neuronal dysfunction and loss, as well as gliotic activity frequently present during neurodegeneration. The proposed studies will validate neuronal and glial MRS biomarkers measured at high magnetic fields by establishing their pathological correlates. The studies will further determine how sensitive these putative biomarkers are to early abnormalities and disease reversal. Pathologically and neurologically well-characterized mouse models of spinocerebellar ataxia type 1 (SCA1) will be studied. In specific aim 1, neurochemical profiles will be obtained longitudinally by high field (9.4 tesla) MRS in cerebella of two mutant mouse lines and controls. One line displays Purkinje cell specific pathology, while the second line displays more widespread involvement. Together they will provide a large dynamic range of neuronal and glial abnormalities, especially with regards to affected GABAergic and glutamatergic systems. Associations will be sought between these MRS markers and histopathological observations in the same brains. Since these mice develop pathology prior to neurological abnormalities, they will also enable assessment of the utility of MRS for early disease detection. In specific aim 2, a conditional SCA1 model will be utilized to reveal the sensitivity of MRS biomarkers to disease reversal. Neurochemical profiles will be obtained by high field MRS in cerebella of the conditional model before and after stopping transgene expression. An almost complete reversal of neurochemical alterations is expected with early intervention, while only a partial recovery is anticipated when transgene expression is stopped during mid-stage disease based on prior experience with this model. Similar to aim 1, MRS findings will be compared to standard histopathology in the same brains. The neurochemical profile approach is expected to provide a multiparametric measure of various aspects of neurodegeneration. If validated, this non-invasive approach has potential to improve management (early detection, disease staging and treatment monitoring) of many neurodegenerative diseases and to facilitate longitudinal pre-clinical trials with model animals. This work intends to establish and validate non-invasive, quantitative imaging measures of cellular alterations in neurodegenerative diseases. Such measures can eventually be used in the clinic for early disease detection, which in turn will facilitate application of treatments to delay the onset of these diseases, as well as for monitoring treatment response. Successful application of such treatments is expected to reduce the burden caused by these diseases on individuals, their families and society. [unreadable] [unreadable] [unreadable]